Biology subjects

Priestley, M.

Publications and source records attributed to Priestley, M..

3 recordsLinked to original sources

bioRxiv2025

CD200R1 is required for the development of γδ 17 T cells

{gamma}{delta} T cells are enriched at barrier sites such as skin, gut and lung, where they protect against cancer and infections and promote healing. They detect diverse ligands in T cell receptor-dependent or independent manners, producing large quantities of pro-inflammatory cytokines. {gamma}{delta} T cells develop in foetal thymi in temporally controlled waves where, unlike {beta} T cells, many {gamma}{delta} T cells adopt their effector fate, becoming either IFN{gamma} or IL-17A-producers ({gamma}{delta}17 T cells). CD200R1 suppresses myeloid cell activity but has also been shown to promote innate lymphoid cell IL-17A production, enhancing psoriasis-like skin inflammation. {gamma}{delta}17 T cells are potent IL-17A producers in skin therefore, the effect of CD200R1 on IL-17A production by {gamma}{delta}17 T cells was investigated. CD200R1 was found to promote IL-17A production by {gamma}{delta} T cells by supporting the development of {gamma}{delta}17 T cells, enhancing IL-17-producing and ROR{gamma}t+ {gamma}{delta} T cell numbers in foetal thymic organ cultures. To fulfil this role, CD200R1 acts either directly on developing {gamma}{delta} T cells, or indirectly on thymic stromal cells. This identifies CD200R1 as a critical novel regulator of {gamma}{delta}17 T cell development in early life, a key process for ensuring immunity, particularly at barrier sites.

immunology↗

bioRxiv2023

Dissection of a non-coding risk locus at 1p36.23 identifies ERRFI1 as a novel gene in the pathogenesis of psoriasis and psoriatic arthritis

BackgroundPsoriasis and its associated inflammatory arthritis Psoriatic Arthritis (PsA) are potentially life-ruining conditions associated with numerous comorbidities. A previously-identified genetic risk association for psoriasis and PsA lies in a non-coding region at chromosome 1p36.23, and as such functional validation is required to determine the genetic mechanism contributing to psoriatic disease risk. Resultsrs11121131 - a variant in tight linkage with rs11121129, the lead GWAS variant for the 1p36.23 association - lies in a putative enhancer active in keratinocytes but not in immune cells. Promoter-capture Hi-C and H3K27Ac HiChIP showed keratinocyte-specific interactions between 1p36.23 and the TNFRSF9/PARK7/ERRFI1 gene locus [~]200Kb upstream of the risk locus. Deletion of the enhancer in HaCat keratinocytes led to a reduction in transcript levels of the gene ERRFI1, a negative regulator of Epidermal Growth Factor Receptor (EGFR) signalling. CRISPR activation of the enhancer also affected ERRFI1 levels, but paradoxically showed that steady-state activation led to repression of ERRFI1, accompanied by significant deposition of H3K27Me3 histone marks at both the enhancer and the ERRFI1 gene locus. ERRFI1 levels were shown to be increased in inflamed skin from a mouse model of psoriasis, further suggesting its involvement in disease. ConclusionsThese data indicate rs11121131 lies in an enhancer which modulates ERRFI1 expression in keratinocytes, providing a likely risk mechanism for the 1p36.23 risk association. ERRFI1 represents a novel gene in the pathogenesis of psoriasis and PsA - improving our understanding of these diseases - and the ERRFI1/EGFR signalling axis may therefore be a target for new treatment modalities for psoriatic disease.

genomics↗

bioRxiv2022

CD200R1 promotes IL-17 production by ILC3s, by enhancing STAT3 activation

Psoriasis is a common chronic inflammatory skin disease with no cure. It is driven by the IL-23/IL-17A axis and TH17 cells but, recently group 3 innate lymphoid cells (ILC3s) have also been implicated. However, the development, and factors regulating the activity of ILC3s remain incompletely understood. Immune regulatory pathways are particularly important at barrier sites such as the skin, gut and lung, which are exposed to environmental substances and microbes. CD200R1 is an immune regulatory cell surface receptor which inhibits proinflammatory cytokine production in myeloid cells. CD200R1 is also highly expressed on ILCs, where its function remains largely unexplored. We previously observed reduced CD200R1 signalling in psoriasis skin, suggesting that dysregulation may promote disease. Here we show that contrary to this, psoriasis models are less severe in CD200R1-deficient mice due to reduced IL-17 production. Here we uncover a key cell-intrinsic role for CD200R1 in promoting IL-23-driven IL-17A production by ILC3s, by promoting STAT3 activation. CD200R1 is expressed on ILC precursors and is particularly high on neonatal ILC3s, suggesting CD200R1 may function during ILC development. Therefore, CD200R1 is required on ILC3s, potentially during their development, to promote IL-23-stimulated STAT3 activation triggering optimal IL-17 production.

immunology↗